<p>Diabetes mellitus (DM), obesity, and metabolic syndrome are related disorders with wide-ranging and devastating effects that are comorbid with many other diseases. Clinical and epidemiological studies have found that type II diabetes mellitus (T2DM), including chronic hyperglycemia and hyperinsulinemia, significantly increases the risk of Alzheimer’s disease (AD) and other forms of dementia in the elderly. Insulin has slightly different functions in the peripheral body than in the central nervous system and the dysregulation of these functions may contribute to the onset and progression of late-life neurodegenerative disease. To investigate cognitive function and AD-related disease pathology, we utilized two different models of key features of diabetes, one model characterized by hyperglycemia resulting from a diabetogenic compound that selectively targets insulin-producing pancreatic β-cells, and the other model based on diet-induced obesity. Additionally, these diabetic models were combined with fractalkine receptor knockout mice (CX3CR1^−/−), a genetic mouse model of inflammation, to explore the additive effects of multiple AD risk factors. The CX3CR1 receptor has been implicated in modulating neuroinflammation associated with AD, and its dysregulation can exacerbate metabolic disturbances and neurodegenerative markers. We found that diabetic-status, regardless of whether it was drug- or diet-induced, resulted in profound impairments in learning and memory and AD-related alterations within the hippocampus.</p>